scholarly journals Acquired Immunity to Chlamydia pneumoniae Is Dependent on Gamma Interferon in Two Mouse Strains That Initially Differ in This Respect after Primary Challenge

2000 ◽  
Vol 68 (2) ◽  
pp. 960-964 ◽  
Author(s):  
Jenni M. Vuola ◽  
Vuokko Puurula ◽  
Marjukka Anttila ◽  
P. Helena Mäkelä ◽  
Nina Rautonen
Keyword(s):  
Genetic Background ◽  
Primary Infection ◽  
Chlamydia Pneumoniae ◽  
Inbred Mouse ◽  
Gamma Interferon ◽  
Mouse Strains ◽  
Acquired Immunity ◽  
Ifn Γ

ABSTRACT The role of gamma interferon (IFN-γ) in a Chlamydia pneumoniae mouse model was studied by in vivo neutralization in two inbred mouse strains. During primary C. pneumoniaeinfection, neutralization of IFN-γ increased both the numbers of bacteria and the pneumonia score in the lungs of C57BL/6 mice but not BALB/c mice. During reinfection, the bacterial counts in the lungs were increased by IFN-γ neutralization in both mouse strains. Thus, the effect of IFN-γ neutralization was dependent on the genetic background in primary infection. However, IFN-γ appeared to be equally important in both mouse strains during reinfection.

scholarly journals Resistance to Acute Babesiosis Is Associated with Interleukin-12- and Gamma Interferon-Mediated Responses and Requires Macrophages and Natural Killer Cells

2003 ◽  
Vol 71 (4) ◽  
pp. 2002-2008 ◽  
Author(s):  
Irma Aguilar-Delfin ◽  
Peter J. Wettstein ◽  
David H. Persing
Keyword(s):  
Nk Cells ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
No Production ◽  
Cytokine Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Crucial Part

ABSTRACT We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO.

scholarly journals Local Immune Responses to Chlamydia pneumoniae in the Lungs of BALB/c Mice during Primary Infection and Reinfection

1998 ◽  
Vol 66 (11) ◽  
pp. 5113-5118 ◽  
Author(s):  
Jenni M. Penttilä ◽  
Marjukka Anttila ◽  
Mirja Puolakkainen ◽  
Aino Laurila ◽  
Kari Varkila ◽  
...  
Keyword(s):  
Primary Infection ◽  
Bacterial Infections ◽  
Chlamydia Pneumoniae ◽  
Mononuclear Cells ◽  
Relative Increase ◽  
Culturable Bacteria ◽  
Ifn Γ ◽  
Tissue Reactions

ABSTRACT Cell-mediated immune (CMI) responses play a major role in protection as well as pathogenesis of many intracellular bacterial infections. In this study, we evaluated the infection kinetics and assessed histologically the lymphoid reactions and local, in vitro-restimulated CMI responses in lungs of BALB/c mice, during both primary infection and reinfection with Chlamydia pneumoniae. The primary challenge resulted in a self-restricted infection with elimination of culturable bacteria by day 27 after challenge. A mild lymphoid reaction characterized the pathology in the lungs. In vitro CMI responses consisted of a weak proliferative response and no secretion of gamma interferon (IFN-γ). The number of lung-derived mononuclear cells increased substantially during the primary infection; the largest relative increase was observed in B cells (B220+). After reinfection, the number of lung-derived mononuclear cells increased further, and the response consisted mainly of T cells. The reinfection was characterized in vivo by significant protection from infection (fewer cultivable bacteria in the lungs for a shorter period of time) but increased local lymphoid reaction at the infection site. In vitro, as opposed to the response in naive mice, acquired immunity was characterized by a strongly Th1-biased (IFN-γ) CMI response. These results suggest that repeated infections with C. pneumoniae may induce Th1-type responses with similar associated tissue reactions, as shown in C. trachomatis infection models.

scholarly journals C57BL/6 and 129 inbred mouse strains differ in Gbp2 and Gbp2b expression in response to inflammatory stimuli in vivo

2019 ◽  
Vol 4 ◽  
pp. 124
Author(s):  
Barbara Clough ◽  
Ryan Finethy ◽  
Rabia T. Khan ◽  
Daniel Fisch ◽  
Sarah Jordan ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Genetic Background ◽  
Inbred Mouse ◽  
Shigella Flexneri ◽  
Protein Translation ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Immune Priming ◽  
Mrna Induction

Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

scholarly journals Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection

2000 ◽  
Vol 68 (12) ◽  
pp. 6567-6573 ◽  
Author(s):  
Joan K. Brieland ◽  
Craig Jackson ◽  
Steve Hurst ◽  
David Loebenberg ◽  
Tony Muchamuel ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Lavage Fluid ◽  
Lung Infection ◽  
Gamma Interferon ◽  
Pcr Analysis ◽  
Interleukin 18 ◽  
Legionnaires Disease ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-γ)-mediated resolution of replicativeLegionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-γ mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior toL. pneumophila infection inhibited induction of intrapulmonary IFN-γ production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-γ and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-γ in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

scholarly journals Peripheral Blood Gamma Interferon Release Assays Predict Lung Responses and Mycobacterium tuberculosis Disease Outcome in Mice

2008 ◽  
Vol 15 (3) ◽  
pp. 474-483 ◽  
Author(s):  
Gillian L. Beamer ◽  
David K. Flaherty ◽  
Bridget Vesosky ◽  
Joanne Turner
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Peripheral Blood ◽  
Diagnostic Tests ◽  
Inbred Mouse ◽  
Gamma Interferon ◽  
Blood Cultures ◽  
Disease Outcome ◽  
Mouse Strains ◽  
Increased Risk ◽  
Ifn Γ

ABSTRACT Current diagnostic tests for tuberculosis (TB) are not able to distinguish active disease from latent Mycobacterium tuberculosis infection, nor are they able to quantify the risk of a latently infected person progressing to active TB. There is interest, however, in adapting antigen-specific gamma interferon (IFN-γ) release assays (IGRAs) to predict disease outcome. In this study, we used the differential susceptibilities of inbred mouse strains to M. tuberculosis infection to evaluate the prognostic capabilities of IGRAs. Using lung and blood cultures, we determined that CBA/J, DBA/2, and C3H/HeJ mice (models of heightened risk of progression to active TB) produced less antigen-specific IFN-γ in response to M. tuberculosis culture filtrate proteins and early secreted antigenic target-6 than the relatively resistant C57BL/6 mouse strain. Additionally, reduced IFN-γ secretion in supernatants reflected a reduced frequency of IFN-γ-responding cells in the lung and blood and not a specific defect in IFN-γ secretion at the single-cell level. Importantly, detection of antigen-specific IFN-γ from blood cultures accurately reflected lung responses, indicating that blood can be an appropriate test tissue in humans. Furthermore, reduced antigen-specific IFN-γ production and low frequencies of IFN-γ-responding cells from peripheral blood predicted increased risk of TB disease progression across genetically diverse TB disease-susceptible mouse strains, suggesting that similar results may occur in humans. The development of efficacious predictive diagnostic tests for humans would lead to targeted therapy prior to progression to active TB, reducing transmission, incidence, and prevalence rates while maximizing the use of public health resources.

scholarly journals Gamma Interferon-Producing CD4+ T Lymphocytes in the Lung Correlate with Resistance to Infection withMycobacterium tuberculosis

2001 ◽  
Vol 69 (4) ◽  
pp. 2666-2674 ◽  
Author(s):  
Alissa A. Chackerian ◽  
Thushara V. Perera ◽  
Samuel M. Behar
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Genetic Locus ◽  
Inbred Mouse ◽  
Gamma Interferon ◽  
Mouse Strains ◽  
C3h Mice ◽  
Ifn Γ ◽  
Resistance To Infection

ABSTRACT The human immune system efficiently limits the replication ofMycobacterium tuberculosis in most infected individuals. Only 5 to 10% of infected people develop clinical tuberculosis, a sign of the inability of the immune system to control the infection. We have studied the C3H/HeJ (C3H) and C57BL/6 (B6) inbred mouse strains, which differ in their susceptibility to tuberculosis, in order to ascertain the immunological determinants of a successful immune response againstM. tuberculosis and to establish a system to identify genes that influence susceptibility to tuberculosis. We found that the resistant B6 mice were able to control infection in both the lung and spleen, while susceptible C3H mice were incapable of limiting bacteria growth, especially in the lung, and succumbed to infection within 4 weeks. We determined that the susceptibility of C3H mice was independent of the Toll-like receptor 4 (tlr4) genetic locus and allelic major histocompatibility complex differences. Although the splenic immune responses were similar in the two mouse strains, the local immune responses in the lungs of the infected mice differed greatly. The pulmonary immune response in resistant B6 mice was characterized by an early influx of both CD4+ and CD8+ lymphocytes that produced gamma interferon (IFN-γ). In contrast, the immune response of C3H mice in the lung was characterized by a delayed and decreased influx of lymphocytes, which produced little IFN-γ. These results suggest an important role for the early appearance of IFN-γ-producing lymphocytes in the lung in resistance to infection with M. tuberculosis.

Mouse Invariant TCR Specific Monoclonal Antibody NKT14: A Novel Tool To Manipulate Invariant NKT Cell Function In Vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3478-3478
Author(s):  
Felix Scheuplein ◽  
Abraham Thariath ◽  
Robert Mashal ◽  
Robert Schaub
Keyword(s):  
Cell Function ◽  
Inbred Mouse ◽  
Inkt Cell ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Specific Monoclonal Antibody ◽  
Cell Disease ◽  
Inkt Cells

Abstract The iNKT cell represents a novel therapeutic target for important hematologic diseases such as sickle cell disease (SCD) and myeloma. While an antibody specifically targeting human iNKT cells is now in a clinical trial, no surrogate reagent that specifically recognizes murine iNKT cells has been previously reported. This abstract defines work on a unique, recently developed antibody specifically directed to the T cell receptor of the mouse iNKT cell. These cells are a small subset of T lymphocytes that share characteristics with adaptive as well as innate immune cells. In contrast to conventional T cells they recognize glycolipid antigens presented on the MHC-I like molecule CD1d. Upon activation they can rapidly release either pro-inflammatory or anti-inflammatory cytokines, depending on stimulus and microenvironment. This enables them to direct downstream immune functions into inflammatory or tolerizing modes. iNKT cell activation has been implicated as a mediator of the chronic inflammation that is found in patients with SCD (Field et al. Blood 121:3321, 2013) suggesting that reduction of activity or iNKT cell depletion may be an effective therapy. The activation of iNKT cells has been shown to have therapeutics effects in multiple hematologic tumors including myeloma, lymphoma, and leukemia (Dhodapkar and Richter Clin.Immunol.140:160, 2011). Until now, the role of iNKT cells in immune regulation has been studied using iNKT cell deficient inbred mouse strains like CD1d and Ja18 knockout mice or with the iNKT cell activating agent alpha-Galactosyl-Ceramide (aGalCer). These tools have weaknesses and limitations. CD1d deficient mice are not only deficient in invariant NKT cells but also other CD1d restricted cells, such as Type 2 NKT cells. Ja18 knockout mice have recently been shown to have a substantial decrease in TCR diversity in addition to their iNKT cell deficiency (Bedel et al.,Nat Immunol. 2012 Jul 19;13(8):705-6.). Furthermore, these mouse strains lack iNKT cells from birth and little is known about pharmacologic suppression in iNKT cell competent mouse strains. Although aGalCer can be used to activate iNKT cells in vivo, it induces a persistent iNKT cell anergy after activation. NKT Therapeutics has developed human iNKT cell specific humanized monoclonal antibodies, one of which is currently being evaluated in a Phase I study in patients with sickle cell disease. The human iNKT cell specific antibodies are not cross-reactive to murine iNKT cells. In order to better understand the potential of pharmacologic modulation of iNKT cell function in pre-clinical disease models, we developed a mouse iNKT specific monoclonal antibody. We have a generated both a depleting version (NKT-14) and by manipulating the FC-function through mutations we have also generated a non-depleting, activating version (NKT-14m). Both are highly specific for mouse iNKT cells and recognize all aGalCer -loaded CD1d tetramer binding cells (Fig. 1A) in multiple inbred mouse strains tested (C57BL/6, BALB/c, NOD, DBA, C3H,NZW, NZW/NZB F1, AKR, SJL and A/J). NKT-14 rapidly and very specifically depletes iNKT cells in vivo (Fig. 1B). NKT-14m can activate iNKT cells in vivo and induces release if IFn-Gamma (Fig. 1C). These novel mouse invariant TCR specific monoclonal antibodies will allow us to better understand the role of iNKT cells in health and disease in order to inform clinical trials of therapeutics which manipulate these unique immune regulatory cells for the treatment of disease. Disclosures: Scheuplein: NKT Therapeutics: Employment. Thariath:NKT Therapeutics: Employment. Mashal:NKT Therapeutics: Employment, Equity Ownership. Schaub:NKT Therapeutics: Employment.

scholarly journals Characteristics of Invasive Candidiasis in Gamma Interferon- and Interleukin-4-Deficient Mice: Role of Macrophages in Host Defense against Candida albicans

1998 ◽  
Vol 66 (4) ◽  
pp. 1708-1717 ◽  
Author(s):  
Rita Káposzta ◽  
Peter Tree ◽  
László Maródi ◽  
Siamon Gordon
Keyword(s):  
Candida Albicans ◽  
Host Defense ◽  
Invasive Candidiasis ◽  
Critical Role ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
In Vivo Studies ◽  
Mouse Strains ◽  
Ifn Γ

ABSTRACT Murine models of invasive candidiasis were used to study the in vivo importance of gamma interferon (IFN-γ) and interleukin-4 (IL-4) in host defense against Candida albicans and to characterize the tissue inflammatory reactions, with special reference to macrophages (Mφ). Knockout (KO) IFN-γ-deficient (GKO) and IL-4-deficient (IL-4 KO) and C57BL/6 parental mouse strains were challenged intraperitoneally with 108 C. albicans blastoconidia. Survival of GKO mice was significantly lower (16.7%) than that of C57BL/6 control (55.5%) and IL-4 KO (61.1%) animals, but was not correlated with the extent of organ colonization. Immunohistological analysis with a panel of myeloid and lymphoid markers revealed multiple renal abscesses, myocarditis, hepatitis, meningoencephalitis, and pneumonia in each strain, with a dominant presence of Mφ. In the absence of IFN-γ, C. albicans induced striking changes in the phenotype of alveolar Mφ and extensive perivascular lymphoid infiltrates in the lung. Impairment in nitric oxide production by peritoneal Mφ was shown only in GKO mice, and they produced Candida-specific immunoglobulin G (IgG), IgM, IgA, and IgG subclasses in lower titers. Our in vivo studies with KO mice elucidate a critical role for IFN-γ, but not IL-4, in host defense against C. albicans.

scholarly journals Role of Gamma Interferon in the Pathogenesis of Severe Schistosomiasis in Interleukin-4-Deficient Mice

2001 ◽  
Vol 69 (12) ◽  
pp. 7445-7452 ◽  
Author(s):  
Anne Camille La Flamme ◽  
Elisabeth A. Patton ◽  
Edward J. Pearce
Keyword(s):  
Severe Disease ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
No Production ◽  
Wild Type ◽  
Fatal Disease ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT In the absence of interleukin-4 (IL-4), infection withSchistosoma mansoni leads to a severe fatal disease rather than the chronic survivable condition that occurs in wild-type (WT) mice. Because the sustained production of NO most closely correlates to weight loss and fatality in infected IL-4−/− mice and because gamma interferon (IFN-γ) is an important inducer of inducible NO synthase, infected IL-4−/− mice were treated with anti-IFN-γ antibodies to determine the role of IFN-γ during schistosomiasis in WT and IL-4−/− animals. When IFN-γ was neutralized, Th2 responses were enhanced and NO production was reduced in both WT and IL-4−/− mice. The decreased NO production correlated with a rescue of proliferation in splenocytes from infected IL-4−/− mice. Furthermore, the neutralization of IFN-γ in vivo improved the gross appearance of the liver and led to a reduction in granuloma size in infected IL-4−/− but not WT mice. However, the neutralization of IFN-γ in vivo did not affect the development of severe disease in infected IL-4−/− mice. These results suggest that while the increased production of IFN-γ does lead to some of the pathology observed in infected IL-4−/− mice, it is not ultimately responsible for cachexia and death.

scholarly journals Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

2006 ◽  
Vol 80 (1) ◽  
pp. 192-200 ◽  
Author(s):  
Ashley L. Steed ◽  
Erik S. Barton ◽  
Scott A. Tibbetts ◽  
Daniel L. Popkin ◽  
Mary L. Lutzke ◽  
...  
Keyword(s):  
Immune Surveillance ◽  
Viral Gene Expression ◽  
Gamma Interferon ◽  
Viral Gene ◽  
Herpesvirus Infection ◽  
Murine Gammaherpesvirus ◽  
Ifn Γ ◽  
Gammaherpesvirus 68 ◽  
Novel Strategy

ABSTRACT Establishment of latent infection and reactivation from latency are critical aspects of herpesvirus infection and pathogenesis. Interfering with either of these steps in the herpesvirus life cycle may offer a novel strategy for controlling herpesvirus infection and associated disease pathogenesis. Prior studies show that mice deficient in gamma interferon (IFN-γ) or the IFN-γ receptor have elevated numbers of cells reactivating from murine gammaherpesvirus 68 (γHV68) latency, produce infectious virus after the establishment of latency, and develop large-vessel vasculitis. Here, we demonstrate that IFN-γ is a powerful inhibitor of reactivation of γHV68 from latency in tissue culture. In vivo, IFN-γ controls viral gene expression during latency. Importantly, depletion of IFN-γ in latently infected mice results in an increased frequency of cells reactivating virus. This demonstrates that IFN-γ is important for immune surveillance that limits reactivation of γHV68 from latency.

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